1. Field of the Invention
The present disclosure relates generally to antibody-based molecules useful as therapeutics for treating various medical conditions. More particularly, the disclosed invention relates to hinge antibodies that are selectively activated in a target cell or tissue so as to treat the medical conditions therein.
2. Description of Related Art
Antibody-based therapeutic agents, including monoclonal antibodies, are emerging as one of the major classes of drugs effective in the treatment of various diseases. Of the top 10 drugs by global sales in 2012, five are therapeutic antibodies, including, HUMIRA™, REMICADE™, RITUXAN™, HERCEPTIN™, and AVASTIN™. Said five drugs grossed about $45 billion around the globe, approximating 60% of the global antibody-based therapeutic agent market in that year. The global market is expected to grow continuously as existing products expand their approved usage and new entrants launch into the marketplace.
Although the field continues to advance, many challenges remain in order to bring more efficacious and affordable antibody-based candidates to the market. One problem associated with current antibody-based therapeutic agents is the poor selectivity of site of action. Monoclonal antibodies and soluble fusion proteins are specific for binding to and neutralizing their intended target molecules (such as antigens and cell surface receptors). However, most target molecules are not specific to the disease site; rather, they may be present in cells or tissues other than the disease site. Accordingly, the therapeutic agent may act in these non-disease normal cells or tissues. This off-target action may result in unwanted side effects. Consequently, developing highly targeted antibody-based therapeutic agents is desirable.
One possible scheme of avoiding off-target action and increasing selectivity is to provide a pro-antibody activatable in the target site. For example, U.S. Pat. No. 8,399,219 and U.S. Patent Application Publication No. 2010/0189651 disclose protease activatable antibodies that are modified by a peptide mask or masking moiety. In these documents, the phage display technique is used to screen peptides or moieties capable of inhibiting/reducing the binding of the functional antibody to its binding target. However, the masking moieties obtained by such methods could not be universally applied to all antibodies for they are identified based on their inhibitory ability toward a specific target. Therefore, it is necessary in their approach to develop a masking moiety for each antibody-based therapeutic agent, which is time consuming, expensive, and complicated. Additionally, the introduction of masking moieties runs the risk of inducing unnecessary immuno response to the subject.
A similar approach is described in U.S. Patent Application Publication No. 2010/0189727, which proposed a masking ligand non-covalently bound to an antigen binding site of an antibody so as to inactivate the antibody. In particular, the masking ligand comprises two copies of the epitope of the antigen to which the antibody specifically binds and a cleavable polypeptide cleavable linker joined to each copy of the epitope. Similar to the phage display technique described above, the masking ligand also needs to be specifically designed with respect to each antibody, and hence the development of such inactivated antibody is also time-consuming and with high cost. Further, since the masking ligand has a high affinity toward the therapeutic antibody, there might be certain masking ligands attached to the antibody after the cleavage of the cleavable polypeptide cleavable linker. These residual masking ligands may hinder the therapeutic action of the antibody.
In view of the foregoing, there exists a need in the art for providing next generation therapeutics that are carefully designed and engineered to possess features such as improved selectivity of site of action as well as enhanced efficacy. Further, such design and engineering schemes shall be applicable to a wide variety of antibody-based therapeutic agents, and would not incur unwanted immuno response.